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Pharmacogenetic Directed Dosing Leads to Optimized Voriconazole Levels in Pediatric Patients Receiving Hematopoietic Stem Cell Transplants Ashley Teusink, PharmD, MBA, BCPS, Alexander Vinks, Kejian Zhang, Stella Davies, Lisa Filipovich, Tsuyoshi Fukada, Parinda Mehta Cincinnati Children’s Hospital Medical Center

Disclosures

•  I have no conflicts of interest to disclose

Learning Objective

•  Recognize the impact of pharmacogenetic directed dosing on the achievement of voriconazole levels

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Voriconazole Mechanism of Action

•  Voriconazole is an extended spectrum triazole antifungal agent

•  Mechanism of action: –  Inhibition of 14-α-sterol demethylase, thus impairing

the synthesis of ergosterol for the cytoplasmic membrane

Voriconazole Spectrum of Activity

5-­‐Fc=flucytosine;  Fluc=Fluconazole;  Vori=Voriconazole;  Posa=Posaconazole;  Itra=Itraconazole;  AMB=Amphotericin  B;  ECH=  Echinocandins;  DD=  dose  dependent    

John  Hopkins  AnIbioIc  Guide  Online  Biol  Blood  Marrow  Transplant.  2004;  10:73-­‐90  

Voriconazole Pharmacokinetics

Clin  Infect  Dis.  2010;  50:  27-­‐36  AnImicrob  Agents  Chemother.  2009:53:  935-­‐44  AnImicrob  Agents    Chemother.  2010:54:  4116-­‐4123  AnImicrobial  Agents  and  Chemother;  56:3032-­‐3042  

Pharmacokine,c  parameter  

Pediatrics   Adults  

Bioavailability   45-­‐80%   96%  

Volume  of  DistribuIon   4.6  L/kg     1.1-­‐1.2  L/kg    

Metabolism   CYP2C19  CYP2C9  CYP3A4  

CYP2C19  CYP2C9  CYP3A4  

Clearance   1.1  -­‐  24  mL/min/kg   166  –  216  mL/min  

EliminaIon  (T  ½)   3.1-­‐29.2  hours   6  hours    

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Voriconazole Efficacy and Safety

§  Associated with the AUC/MIC ratio §  Low voriconazole exposure and trough

concentrations have been linked to therapeutic failure in both treatment and prophylactic setting

§  High voriconazole plasma concentrations (> 5.5 mg/L- 6 mg/L) have been linked to various adverse effects

Clin  Infect  Dis  2002:563-­‐571  Agents  Chemother.  2012:56:3032-­‐3042  Bone  Marrow  TransplantaIon:2007:451-­‐56  Ther  Drug  Monit.  2012:77  Eur  J  clin  Microbiol  Infec  Dis.  2011:  283-­‐287      

Our Pilot Study

§  Patients for whom voriconazole was determined to be a suitable antifungal prophylaxis underwent testing for CYP2C19 genotype

§  Voriconazole was started at 5 mg/kg/dose q12h §  Prior (0.5 to 1 hour) to the 9th dose a voriconazole

serum concentration was drawn §  Target trough: 1-5 mg/L

§  Doses were adjusted per protocol until target range was achieved

Our Pilot Study

•  Adjustments made to achieve target voriconazole levels: Level < 1 mg/L •  Increase daily dose by 25% (level to be repeated prior to 9th new

dose) Levels ≥ 1 mg/L and ≤ 5 mg/L •  Make no changes to therapy (repeat level every week x 1 month, then

every 2 weeks for months 2-3) Levels > 5 mg/L

•  Two doses held and then restarted at 50% of the previous dose (level to be repeated prior to 9th new dose)

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Our Pilot study results

Results   Number  (range  or  %)  Total  number  of  paIents   25  

Median  age  in  years   7  (0.8-­‐23)  

CYP2C19  genotyping  

       Extensive  metabolizers   17  (68%)  

       Intermediate  Metabolizers   3  (12%)  

       Poor  metabolizers   2  (8%)  

       Not  tested   3  (12%)  

Our Pilot study results

Results   Median  (range)  Voriconazole  serum  concentra,ons   1.1  mg/L  (<0.1-­‐6.1)  

Days  to  therapeu,c  level  

     Overall   30  (3-­‐65)  

     Extensive  metabolizers   30  (5-­‐65)  

     Intermediate  metabolizers   51.5  (47-­‐56)  

     Poor  metabolizers   11  (11)  

Our Pilot Study Results

Dose  of  voriconazole  required  to  reach  therapeu,c  level  (mg/kg/day)  

         Overall   12.5  (5.4-­‐36.3)  

         Extensive  metabolizers   13.3  (5.4-­‐36.3)  

         Intermediate  metabolizers   16.3  (11-­‐18.9)  

         Poor  metabolizers   10.6  (9.8-­‐11.4)  

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Pharmacogenetic Directed Dosing Leads to Optimized Voriconazole Levels in Pediatric Patients Receiving Hematopoietic Stem Cell Transplants

Background

•  Aims §  Primary: Determine if genotype directed initial

voriconazole dosing would result in decreased time to reach desired target range

§  Secondary: Determine if the incidence of adverse effects increase as a result of higher initial dosing

Methods

•  All patients receiving voriconazole prophylaxis at our institution between June 2013 and September 2013 were followed prospectively

•  All patients were genotyped for CYP2C19 polymorphisms

•  Initial voriconazole dose decided on based on patients genotype

•  Dose changes made based on protocol

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Methods

Results

Number  (range  or  %)  

Total  number  of  paIents    21  

Median  age  in  years   10.7  (0.8-­‐26.4)  

CYP2C19  genotyping  

       Extensive  metabolizers   11  (52.4%)  

       Intermediate  Metabolizers      7  (33.3%)  

       Poor  metabolizers      0  (0%)  

     Ultra-­‐rapid  metabolizers      2  (9.5%)  

     Unknown      1  (4.8%)  

Median  (range)    

Voriconazole  serum  concentra,ons  

1.3  mg/L  (0.1-­‐5.3)  

Days  to  therapeu,c  level  

     Overall   8  (2-­‐47)  

     Extensive  metabolizers   7  (3-­‐47)  

     Intermediate  metabolizers   6  (3-­‐16)  

     Poor  metabolizers   N/A  

     Ultra-­‐rapid  metabolizers   8.5  (8-­‐9)  

Results

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Results

Conclusions

•  Our results show that CYP450-2C19 genotype directed initial dosing and subsequent dose adjustments per the algorithm can successfully achieve prophylactic voriconazole target levels in pediatric patients undergoing HSCT

•  Strongly recommend genotype directed dosing in HSCT and establishment of center-specific protocol

Audience Response Question RJ is a 5-year-old male being transplanted for hemophagocytic lymphohistiocytosis (HLH). His primary physician is writing his transplant preparative and supportive medication orders now. The physician calls you to determine what dose of voriconazole they should start for RJ’s fungal prophylaxis. You look in his chart and discover RJ’s CYP2C19 genotype is *2/*2. What do you recommend? A.  Start voriconazole 4 mg/kg/dose every 12 hours. Draw

a voriconazole level prior to the 4th dose B.  Start voriconazole 5 mg/kg/day divided every 12 hours.

Draw a voriconazole level prior to the 4th dose C.  Start voriconazole 5 mg/kg/dose every 12 hours. Draw

a voriconazole level prior to the 9th dose D.  Start voriconazole 9 mg/kg/dose every 12 hours. Draw

a voriconazole level prior to the 9th dose

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Acknowledgements •  Dr. Parinda Mehta and Dr. Stella

Davies as well as the entire physician group at CCHMC

–  Jack Bleesing –  Sharat Chandra –  Javier El-Bietar –  Alexandra Filipovich –  Michael Grimley –  Sonata Jodele –  Michael Jordan –  Pooja Khandelwal –  Ashish Kumar –  Rebecca Marsh –  Kasiani Myers

•  The bone marrow transplant nurse practitioners

–  Rachel Ekstrand –  Jodi Jacobs –  Stacey McLean –  Rich Tarin –  Kathy Turner

•  Heme/Onc/BMT decentralized pharmacists

–  Nick Ambrosino –  Ashley Bedel –  Dan Demopoulous –  Wiyanna Kramer –  Steve Mayer –  Nancy Nirody –  Kori Talbott –  Carla Wallace

Questions?

References �  John Hopkins Antibiotic Guide Online Edition. Wingard JR, Leather H. Biol Blood Marrow Transplant. 2004; 10:73-90 �  Neely M, Rushing T, Kovacs A, et al. Voriconazole pharmacokinetics and pharmacodynamics in children. Clin Infect Dis.

2010; 50: 27-36 �  Karlsson M, Lutsar I, Milligan P. Population Pharmacokinetic analysis of voriconazole plasma concentration. Antimicrob

Agents Chemother. 2009:53: 935-44 �  Walsh T, Driscoll T, Milligan P et al. Pharmacokinetics, safety and tolerability of voriconazole in immunocompromised children.

Antimicrob Agents Chemother. 2010:4116-4123 �  Friberg L, Ravva P, Karlsson M. Integrated population pharmacokinetics analysis of voriconazole in children, adolescents and

adults. Antimicrobial Agents and Chemotherapy; 56:3032-3042 �  Denning D, Ribaud P Milpied N, et al. Efficacy and Safety of Voriconazole in the Treatment of Acute Invasive Aspergillosis.

Clin Infect Dis 2002:563-571 �  Imke B, Tom W, Martine J et al. Highly variable plasma concentrations of voriconazole in paediatric haematopoietic stem cell

transplantation patients: Therapeutic drug monitoring is indispensable. Antimicro Agents Chemother. 2012: �  Trifilio S, Singhal S, Williams S et al. Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in

patients on prophylactic voriconazole �  Chen J, Chan C, Colantonio D et al. Therapeutic drug monitoring of voriconazole in children. Ther Drug Monit. 2012:77 �  Spriet I, Casaert K, Renard M et al. Voriconazole plasma levels in children are highly variable. Eur J clin Microbiol Infec Dis.

2011: 283-287 �  Smith J, Safdar N, Knasinski V et al. Voriconazole therapeutic drug monitoring. Antimicrobial agents and chemotherapy 2006:

1570-72 �  Miyakis S, Van Hal S Ray J et al. Voriconazole concentrations and outcome of invasive fungal infection. Clin Microbiol Infect

2010: 927-933. �  Pascual A, Calandra T, Bolay S et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves

efficacy and safety outcomes. Clin infect Dis. 2008:201-211 �  Imhof A, Schaer DJ, Schwarz U. Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring.

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